Organic compounds and process



Unitecl States Patent ORGANIC COMPOUNDS AND PROCESS I John A. Hogg, Kalamazoo Township, Kalamazoo County, Philip F. Beal, Portage Township, Kalamazoo County, and Frank H. Lincoln, Jr., Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Compauy, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application June 11, 1956, Serial No. 590,368

6 Claims. (Cl. 260-397.45) V The present invention relates to novel steroid coin- VIIIa VIIIb R=acyl 2,813,111 Patented Nov. 12, 1957 ice pounds and is more particularly concerned with 140:- methyl-l7a,21-dihydroxy-4-pregnene-3,1 LZO-trione (14apregnene-3,20-dione (14a-methylhydrocortisone), the 21- esters thereof and a process for the production thereof, The novel compounds and the process of production thereof can be represented by the following formulae:

CHgOR" wherein M is a metal selected from the group consisting of lithium, sodium, and potassium, R and R are alkyl groups containing from one to eight carbon atoms, inclusivefand R" is selected from the group consisting of hydrogen and the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

The process of the present invention comprises: treating 14a-methyl-ll-ketoprogesterone (I) with a loweralkyl oxalic acid ester in the present of an alkali-metal base to obtain the corresponding alkali-metal enolate of 21 lower alkyl oxalyl-l4a-methyl-11-ketoprogesterone (II); treatingthe thus-obtained alkali-metal enolate (II) with bromine to obtain the corresponding l4u-methyl-11- keto-2l, 21-dibromo-2l-lower-alkyloxyoxalylprogesterone (III); treating the thus-produced dibromo compound (III) with an alkali-metal alkoxide in an alkenol, preferably wherein the alkoxy group of the alkali metal alkoxide and the alkanol are identical and contain from one to eight carbon atoms, inclusive, to give the corresponding 14oz methyl 3,11-diketo-4,17()-pregnadien-21-oic acid alkyl ester (IV); treating the thus obtained l4a-methyl-- 3,1l-diketo-4,17(20)-pregnadien-2l-oic acid alkyl ester (IV) with a secondary cyclic amine, such as pyrrolidine, morpholine, piperidine, or the like, to form the. corresponding 3-enamine, illustratively 3-pyrrolidyl-14a-methyl-l1-keto-3,5,l7(20)-pregnatrien-21-oic acid methyl alkyl ester (V); reducing the thus-produced 3-pyr'rolidyl enamine (V) with a metal hydride, such as lithium aluminum hydride, sodium borohydride, or the like, to obtain 3 pyrrolidyl 14a methyl-11fl,21-dihydroxy-3,5,l7 (20)-pregnatriene (VI); hydrolyzing the thus-produced 3 pyrrolidyl l4a-methyl-l1,8,21-dihydroxy-3,5,17(20)- pregnatriene (VI) with a base produced the corresponding 14a-methyl-11/3,21-dihydroxy-4,l7(20)-pregnadien-3- one (VIIa); esterifying the thus-produced 14u-methyl- 1lfi,21-dihydroxy-4,17(20)-pregnadien-3-one withv a halide or anhydride of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, produced the corresponding l4a-methyl-1lfi-hydroxy-Z1-acyloxy-4,17(20)-pregnadien-3-one (VIIb); treating the thus-produced l4amethyl 11B hydroxy-2l-acyloxy-4,17(20)-pregnadien-3-one (VHb) with osmium tetroxide in the presence of a peroxide such as hydrogen peroxide and thereafter treating the resulting crude product with sodium sulfite produced 1401 methyl 11fl,17a,21-trihydroxy-4-pregnene-3,20-dione (VIIIa); esterifying 14a-methyl-11fi,17a,21-trihydroxy-4-pregnene-3,20-dione (14a-methylhydrocortisone) with a halide or anhydride of an organic carboxylic acid, preferably of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, produces the 21-esters of 14a-methylhydrocortisone (Ma-methyl- 115,170: dihydroxy 21 acyloxy-4-pregnene-3,20-dione, compound VIIIb). Oxidation of 14a-methylhydrocortisone 21-acylate with chromic anhydride or an alkali metal dichromate in acetic acid produces the corresponding 14a-methylcortisone 21-acylate (l4u-methyl-l7a-hydroxy- 21-acyloxy-4-pregnene-3,11,20-trione, compound IXa). Hydrolysis of l4a-methylcortisone 21-acylate with a base,

preferably in a nitrogen atmosphere, produces the free diol, 140a methyl 17a,2l-dihydroxy-4-pregnene-3,l1,20- trione (14amethylcortisone, compound IXb).

It is an object of the instant invention to provide 14amethylcortisone, l4a-methylhydrocortisone, and the 21- esters thereof, especially those of hydrocarbon carboxylic acids containing from one to twelve carbon atoms, inclusive. It is another object of the instant invention to provide a process for the production of these Hot-methylcortisone and 14a-methylhydrocortisone products and also to provide the intermediates necessary to produce such l4a-methylcortisone and 14a-methylhydrocortisones. Other objects will be apparent to those skilled in the art to which this invention pertains.

The new compounds, 14u-methylcortisone and 14amethylhydrocortisone, are adrenocortical hormones, supe rior to the corresponding cortisone and hydrocortisone, having a high potency, especially in rheumatoid arthritis and minimal side efifects. They are highly anti-inflammatory agents and can be used in oral or parenteral preparations such as tablets and injectable preparations. They are also useful for the preparation of topically applied ointments, as drops for eye, ear, or nose inflammatory conditions, as ingredients in dentifrices for inflammatory conditions of the gingiva, as active ingredients in bougies and suppositories for inflammatory vaginal and rectal conditions, and the like.

The starting material for the instant compounds is 14mmethyl-ll-ketoprogesterone, known in the art [Voser et al., Helv. Chim. Acta 36, 299 (1953) Kyburg et al., Helv. Chim.Acta 36, 1891 (1953)].

In carrying out the process of the instant invention, the procedure of Patents 2,683,724, 2,735,856, and of application S. N. 307,385, filed August 30, 1952, issued as Pat. No. 2,774,776, can be followed except that the starting material is 14a-methyl-ll-ketoprogesterone instead of 11- ketoprogesterone.

' The following examples are illustrative of the detailed process and products of the present invention, but are not to be construed as limiting.

Example 1.-Sodium enolate of 14a-methyl-1I-kelo-2I- ethoxyoxalylprogesterone To a mixture of 3.4 milliliters of a 3.4 normal ethanolic sodium ethoxide solution (0.0116 mole), 0.45 milliliter of absolute ethanol, and twenty milliliters of dry benzene, said mixture previously having been distilled until eight milliliters of distillate had been collected and then cooled, was added 2.3 milliliters (0.0151 mole) of ethyl oxalate and a solution of 3.42 grams (0.01 mole) of Mot-methylll-ketoprogesterone in 38 milliliters of dry benzene. The solution became turbid and a yellow precipitate formed. The reaction mixture was stirred for ninety minutes, 55 milliliters of ether was then added thereto, and stirring was continued for a period of sixty minutes, whereafter a -milliliter portion of ether was added thereto. The thus-formed yellow precipitate of the sodium enolate of 14a-methyl-1l-keto-21-ethoxyoxalylprogesterone was filtered, washed with three fifty-milliliter portions of ether, and after drying found to weigh 3.80 grams. The ether wash contained 0.56 gram of unreacted m nnbr dlketoprogesterone. The yield of the sodium enolate of 14u-methyl-1l-keto-21-ethoxyoxalylprogesterone was 81 percent of the theoretical or practically quantitative calculated on the reacted l4a-methy1-1l-ketoprogesterone. The presence of a sodium enolate was verified by the extreme solubility of the product in water and by a positive ferric chloride test for enols as exhibited by the formation of a bright red color when the product was dissolved in alcoholic and aqueous ferric chloride solutions.

Example 2.P0tassium enolate of 14a-methyl-1 1-keto- 21 -meth oxy oxaly l progesterone In the same manner as shown in Example 1, reacting l4u-methyl-1l-ketoprogesterone with methyl oxalate in the presence of methanolic potassium methoxide solution yielded the potassium enolate of 14a-methyl-l1-keto-2'1- m'ethoxyoxalylprogesterone.

Inthe same manner given in Examples 1 and 2, reacting .14a-methyl-1l-ketoprogesterone with alkyl oxalate, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl oxalate in the presence of an alkali metal base, for example, lithium ethoxide, sodium methoxide, potassium butoxide and the like results in the corresponding lithium, potassium, or sodium enolate of 'l4a-methyl-11-keto-alkyloxyoxalylprogesterone in which the alkyl group has from one to eight carbon atoms, inclusive, as exemplified above.

Example 3.14a-methyl-11-keto-21,21-dibr0m0-21 ethoxy oxalylprogesterone To'a stirred solution of 4.64 grams (0.01 mole) of the sodium enolate of l4a-methyl-1bketo-Zl-ethoxyoxalylprogesterone and two grams of potassium'acetate in seventy milliliters of glacial acetic acid was added 3.09 grams (1.00 milliliter; 0.0193 mole) of bromine dropwise at room temperature. When the addition was complete, the reaction mixture was mixed with a large volume of water. The aqueous layer was then decanted from the precipi- Etated viscous yellow product which was thereafter dis- :solved in alcohol and reprecipitated as ;a white solid by .the dropwise addition of water. The yield of thus-produced 14a-methyl-1 l-keto-Z1,2l-dibromo-2l-ethoxyoxalylprogesterone, after filtering and drying, was 4.1 grams, a yield of seventy percent of the theoretical.

Example 4 .1 4a-methyl-1 1-ket0-21,2]-dichl0r0 21- methoxyoxalylprqgesterone 'In the same manner given in Example 3,-treating'the potassium enolate of 14a-methyl-lI-keto-ZI-methoxyoxalylprogesterone with chlorine, dissolved in carbon tetrachloride, produced 14a-methyl-11-keto-2l',2l-dichloro-Zlmethoxyoxalylprogesterone.

In the same maner as shown in Examples 3 and 4, "treating the alkali-metal enolates of l4a-methyl-l1-keto- 21-alkoxyoxalyl progesterone with bromine-or chlorine is .productive ofother 14a-methyl-1l-keto-2l,2l-dihalo-2lvalkoxyoxalylprogesterones wherein the halo atom is ,bro-

mine or chlorine. Thus produced 14a-methyl-11-keto-21, 21dihalo-21-alkoxyoxalylprogesterones include: 140:- methyl-1 l-keto 21,21-dibromo-2l-methoxyoxalylprogesterone, l4otmethy1-1 1-keto-21,21-dibromo'-2 1 -propoxyoxalylprogesterone, 14a-methyl-1l-keto 21,21-dibromo-2lisopropoxyoxalylprogesterone, 14a-methy1-1l;keto-2l,2ldibromo 21 butoxyoxalylprogesterone, 14a-methy1-1 lketo Z1,21-dibromo-2l-amyloxyoxalylprogesterone, 14amethyl-1lketo-2l,21 dibromo-2l-hexyloxyoxalylprogesterone, l4a-methyl-ll-keto-21,2l-dibromo 2l-heptyloxy- 'oxalylprogesterone, l4a-methyl-l l-keto 21,2 l-dibromo- 2 l-octyloxyoxalylprogesterone, 14u-methyl-l 1-keto 21,2l-

*dichloro 21 ethoxyoxalylprogesterone, l4a-methyl-11- "item-21321 dichloro-21-propoxyoxalylprogesterone, 14a- K methyl-1 1-keto-21,21-dichloro-21-isopropoxyoxalylprogesterone, ;14a-methyl-1 1 -keto-2 1,21 dichloro-Z l' bntoxyox- "alylprogesterone, -14a-methyl-11'-keto 21,2l-dichloro-21- Example 5 ,;1 4a-methy l-3-1 1-diketp -4,I7(2 0) preg: na diemZLoic acid methyl ester To a solution of 6.04 grams (0.01 mole) of l4a-meth yl-l1-keto-2l,21dibromo -21 ethoxyoxalylprogesteror ie in milliliters of methanol was added"'3. 2 l grains (0.06 mole) of commercial grade sodium rriethoxide. The resulting admixture was maintained for three' h'ours at about 2 5 degrees centigrade, whereafter the whole was diluted with water and then extracted with two pertions of methylene chloride. The methylene chloride extracts were dried with anhydrous sodium sulfate and the solvent was thereafter distilled at atmospheric pressure, leaving a quantitative yield of 3.74 grams of 141g:- methyl-3,1 1-diketo-,4, 17 (20)-pregnadien-21-oic acid m ethyl ester as an oil. This oil was dissolved in fifty milliliters of benzene and chromatographed over a column of grams of Florisil synthetic magnesium silicate. The column was developed with 400-milliliter portions of solvent of the following composition and orderz th re portions of methylene chloride, five portions of methylene chloride plus five percent acetone, and one portion of acetone. The methylene chloride plus five percent acetone eluates were combined and the solvent was removed therefrom leaving 1.5 grams of crystalline Mag-methyl- 3,11-diketo-4,17(20)-pregnadien-21-oic acid methyl Example 6.-14a-methyl-3,I1-diketoe4-17(20)-pregnadien-4-0ic acid ethyl ester In the same manner given in Example 5, treating 14ame thyl-11-keto-21,21 dich1oro-21 -.methoxyal ylprogesterone, dissolved in ethanol, with sodium ethoxide pro- .duced 14a methyl 3,11-diketo-4,17(20) pregnadien 2lin tertiary butyl alcohol, lithium methoxide in methanol,

sodium octoxide in octanol and the like, produces the corresponding 14a methyl 3,1l-diketo 4,l7( 20) pregnadien-Zl-oic acid alkyl esters, whereinthe alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, hexyl, heptyl, octyl, and the l ike.

Example 7.14a methyl 11B, 21-dihydr0xy-4;1;7(20)- pregnadien-3-one and its conversion to 1.4u-methyl-11flhydr xy-21-acet0xy-4J 7(20) -pregnadien-3-one A solution of 3.12 grams of 14u-methyl-3,1l-dike to- 4,1'7(20)-pregnadien-21-oic acid methyl ester and three milliliters of pyrrolidine in sixty milliliters of he ene was'heated at its refluxing temperature for one hour. the concomitant removal of the water of reactiomproducing 3 (N-pyrrolidyl)-14a-methyl-ll-keto-3,5,l7(20)- pregriatrien-Zl-oic acid methyl ester. The solventwas distilled from the resulting mixture at reduced pressure and the residue dissolved in a mixture of fifteen milliliters of benzene and ten milliliters of ether.

To this solution of 3-(N-pyrrolidyl)-14 methyl-11- keto-3,5,17(20)-pregnatrien-21-oic methyl ester was added 1.1 grams of lithium aluminum hydride suspended in milliliters of ether. The resulting solution was stirred for 1.5 hours at about 26 degrees centigrade. Ten milliliters of ethyl acetate followed .by liters of water were added to the solution and the solvent ,was distilled therefrom at reduced pressure to give a residue, consisting essentially of inorganic salts and 3- pyrrolidyl 14cc methyl 11B,21-dihydroxy-3,S,17(20)- pregnatriene.

This residue was suspended in 200 milliliters of methanol and 35 milliliters of a five percent aqueous sodium hydroxide solution was added to the suspension. The whole was then heated at forty to 45 degrees centigrade for ten minutes. The cooled mixture was neutralized with acetic acid and the methanol distilled therefrom. The residue was stirred with fifty milliliters of concentrated hydrochloric acid. The methylene chloride solution was separated from the aqueous layer, which was then extracted with another portion of methylene chloride, and the extract added to the original methylene chloride solution. The solvent was evaporated from the extractsleaving 2.98 grams of crude l4a-methyl- 115,2 l-dihydroxy-4, l7 20) -pregnadien-3-one.

The 2.98 grams of 14a-methyl-1119,21-dihydroxy-4, l7(20)-prcgnadien-3-one thus obtained was treated with five milliliters of acetic anhydride in ten milliliters of pyridine at 26 degrees centigrade for four hours. The resulting mixture was mixed with ten milliliters of water with cooling to hydrolyze the excess acetic anhydride, and the solution extracted with methylene chloride. The

extract was washed with dilute hydrochloric acid, water,

I acetoxy-4,l7 (20)-pregnadien-3-one.

Example 8.14cc methyl 11B,21-dihydr0xy-4,17(20)- 'pregnadien-3-0ne and its conversion to 14a-methyl- IB-hya'roxy-ZI -benzoyloxy-4,1 7 (20 -pregnadien-3-one 'In the manner given in Example 7, 14oc-methyl-3,11- diketol,17(20)-pregnadien-21-oic acid ethyl ester was heated to reflux with morpholine in methanol solution to give 3 (N-morpholinyl)-l4o-methyl-11-keto-3,5,l7(20)- pregnatrien-ZO-oic acid ethyl ester which was reduced .with lithium aluminum hydride to give B-(N-morpholinyl) 14a methyl-l15,2l-dihydroxy-3,5,l7(20)-pregnatriene Hydrolyzing 3 (N-morpholinyl) 14a-methyl- 11 3,21-dihydroxy-3,5,17(20)-pregnatriene with aqueous ethanolic potassium hydroxide solution as shown in Example 7 yielded 14a-methyl-l1}3,21-dihydroxy-4,l7(20)- pregnadien-3-one.

' Treating the thus obtained l4a-methyl-ll 3,2l-dihydroxy-4,17(20) pregnadien-3-one with benzoyl chloride in pyridine solution yielded l4a-methyl-llfi-hydroxy-Zlbenzoyloxy-4,17(20) -pregnadien-3-one.

In the same manner given in Examples 7 and 8, treating the -14a-methyl-3,11-diketo-4,17(20)-pregnadien-2loic acid alkyl esters of Examples 5 and 6 with a secondary cyclic amine such as pyrrolidine, substituted pyrrolidine, 'morpholine, homo-morpholine, substituted oxazolidine, pipen'dine or the like produces the corresponding 3-(N- tertiary cyclic enamino)-14a-methyl-11-keto-3,5,17(20)- pregnatrien-Zl-oic acid alkyl ester which by reduction with a metal hydride such as lithium aluminum hydride, sodium borohydride or the like produces the correspond- -ing,3-(N-tertiary cyclic enamino)-14a-methyl-1lB,21-dihydroxy-3,5,17(20)pregnatriene which by hydrolysis with a base, such-as lithium, sodium, potassium, calcium, barium or other alkali or earth alkali hydroxide, preferably hydroxides of the alkali metals in aqueous alcoholic solution-or suspension produces l4m-methyl-lll3,2l-dihydroxy-4, l7(20)-pregnadien-3-one.

--:Est erificati'on of the thus-obtained l4a-methyl-l1p,21- dihydroxy-4,l7 (20) -pregnadien-3-one with an acid anhydn'de such as, for example, propionic, butyric, valeric,

Example 9.14a-methyl11}8,17a,21-trihydr0xy 4 pregnene-3,20-di0ne (14a-methylhydr0c0rtis0n) To a stirred suspension of 0.128 gram (0.00033 mole) of l4a-methyl-ll 8-hydroxy 21 acetoxy-4,17(20)-preg- ,nadien-3-one in two milliliters of tertiary butyl alcohol was added 0.26 milliliter of a 2.6 molar solution of hydrogen peroxide in tertiary butyl alcohol and 0.30 milliliter of a solution of 1.00 gram of osmium tetroxide in 100 milliliters of tertiary butyl alcohol. An additional 0.50 milliliter of the above-described osmium tetroxide solution was added to the reaction mixture during the next thirty hours. After the first four hours of reaction time the reaction mixture darkened and became homogeneous. The reaction mixture was stirred and maintained at room temperature for an additional 84 hours, whereafter Water and methylene chloride were added thereto. The Whole was distilled at reduced pressure to remove the organic solvents and the product was extracted from the residue with methylene chloride, whereafter the extract was freed of solvent by evaporation. The residue,

. after dissolvingin a mixture of five milliliters of methanol and one milliliter of a solution of 0.30 gram of sodium sulfite in five milliliters of water, was heated on a steam bath for thirty minutes. The l4a-methyl-llfi,l7a,2ltrihydroxy-4-pregnene-3,20-dione was separated therefrom by extraction with methylene chloride, which was thereafter removed by distillation in vacuo. The residue, 104 milligrams, was three times recrystallized from acetone- Skellysolve B hexanes to give 42 milligrams of 14u-methyl-l1fl,17u,21-trihydroxy 4 pregnene-3,20-dione (14amethylhydrocortisone). The infrared absorption spectra measured in both Nujol, chloroform and carbon tetrachloride confirmed the above postulated structure.

In the same manner as shown in Example 9, other 21- esters of 4,2l-dihydroxy-4,17(20)-pregnadien-3-one when treated with hydrogen peroxide in the presence of osmium tetroxide in a suitable solvent such as tertiary butyl alcohol or the like undergo the oxidative hydroxylation to produce l4a-methyl-11;3,17a,2l-trihydroxy 4 pregnene- 3,20-dione. Useful esters for this reaction are the propionate, butyrate, isobutyrate, valerate, hexanoate, heptanoate, octanoate, benzoate, phenylacetate, toluate, cyclopentylpropionate or the like 2l-esters of Mix-methyl- '1 1/3,2 l-dihydroxy-4, 17 (20 -pregnadien-3 -one.

' Example 10.-14cz methyl-11 3,17a,21-trihydroxy-4-pregnene-3,20-di0ne 21 -acetate (14a-methylhydr0c0rtis0ne 21 acetate) To a solution of 0.7 gram of 14a-methyl-1lB-hydroxyfive milliliters of dry pyridine, three milliliters of dry tertiary butyl alcohol solution containing 0.7 gram of N- .methylmorpholine oxide peroxide and ten milligrams of osmium tetroxide, in that order. The resulting solution was stirred at between 25 and thirty degrees Centigrade for eighteen hours. Thereafter milliliters of water was added to the mixture, the mixture extracted thoroughly with methylene chloride, the methylene chloride solution washed with water, five percent dilute hydrochloric acid, five percent aqueous sodium bicarbonate,

,water, and then dried over anhydrous sodium sulfate. 75,,

The solvent was distilled from the dried solution at reduced pressure. The crude residue was dissolved in methylene chloride and poured over a column of ten grams of Florisil synthetic magnesium silicate and developed with Skellysolve B hexane in acetone solution containing from ten to twenty percent acetone. The Skellysolve B plus twelve percent acetone and Skellysolve B plus fifteen percent acetone fractions were combined and evaporated, and the residue repeatedly recrystallized from methanol to give l4a-methyl-l1;3,l7a-dihydroxy-21 acetoxy-4-pregnene-3,20-di0ne.

In the same manner as shown in Example 10 reacting other 14a-methyl-1 1,8-hydroxy-21 acyloxy-4,17(20) -pregnadien-3-one as produced in Examples 7 and 8 with osmium tetroxide and N-methylmorpholine oxide .peroxide or other secondary amino oxide peroxide compounds in tertiary butyl alcohol solution in the presence of pyridine yields the corresponding 21-ester of 14amethyl-l 1 B, 17 a,21-trihydroxy-4-pregnene-3,20-dione.

Example 11.-14ot-methyl-11B,1701,21 trihya'i'oxy-4-pregnene-3,20-dine 2'1-pr0pi0'na te Two hundred milligrams of 1'4ot-methyl-11fi,17u,21- trihydroxy-4-pregnene-3,20-dione (Ma-methylhydrocortisone), dissolved in two milliliters of pyridine were admixed with two milliliters of propionic anhydride. The mixture was allowed to stand at room temperature (about 25 degrees centigrade) for a period of eight hours and thereupon diluted with fifty milliliters of water and extracted with three ten-milliliter portions of methylene chloride. The methylene chloride extracts were dried over anhydrous sodium sulfate, evaporated and the residue recrystallized three times from methanol to give 140:- methyl 115,17a,21-trihydroxy-4 pregnene-3,20-dione 21- propionate (Ma-methylhydrocortisone 21-propionate).

In the same manner as shown in Example 11, reacting 14cc methyl-1lB,17ot,2l-trihydroxy 4 pregnene-3,20- dione (Mat-methylhydrocortisone) in pyridine solution with (a) butyric anhydride yielded Mot-methylhydrocortisone butyrate,

(b) valeric anhydride yielded I ia-methylhydrocortisone valerate,

(c) hexanoyl chloride yielded Mot-methylhydrocortisone hexanoate,

(d) heptanoyl chloride yielded Mot-methylhydrocortisone heptanoate,

(e) octanoyl bromide yielded Mot-methylhydrocortisone octanoate,

(f) toluyl chloride yielded I la-methylhydrocortisone toluate,

(g) phenylpropionyl chloride yielded I ia-methylhydrocortisone phenylpropionate (h) B-cyclopentylpropionyl chloride yielded methylhydrocortisone fi-cyclopentylpropionate,

(i) cinnamyl bromide yielded Mot-methylhydrocortisone cinnamate,

(j) hemisuccinyl chloride yielded Mot-methylhydrocortisone acid succinate, I

(k) 2-fur0yl chloride yielded Mat-methylhydrocortisone 2-furoate,

(l) toluenesulfonyl chloride yielded Mot-methylhydrocortisone toluenesulfonate, I

(m) nicotinyl chloride yielded Mot-methylhydrocortisonenicotinate, and

(-n) trimethylacetyI-chloride yielded 14u-methy1hydrm cortisone trimethylacetate. v

In'the same manneras shown -in Examples 11 through 13, reacting other anhydrides or acid halides of an organic carboxylic, preferably of a hydrocarboncarboxylic acid with 14a-methylhydrocortisone produces the corresponding Mot-methylhydrocortisone 21-esters, such as, for example, the ZI-triethylace'tate, dineopentylacetate, phenylacetate, tertiary butyla'cetate, crotonate, ac'r'ylate, chloroacetate, bromoacetate, iodoacetate, fluoroacetate, acid tartra'te, acid maleate, para bromohenzenesulfonate, 'benzenesulfonate, or the like, of M t-methylhydrocortisone.

Example 14.-14a-methylc0rtis0ne 21-acetate (Ma-methyl 1704,21 dihydroxyt-pregnne -'3,1-1,20-trione 21 acetate) A solution was prepared containing 0.2 gram of 14amethylhydrocortisone acetate (14a-methyl--I1fl,l7a,2I- t'rihydroxy-4-pre'gnene-3,20-dione ZI-acet'ate), milligrams of sodium dichromate, 0.5 milliliter of water and 'five milliliters of acetic acid. mixture was allowed to stand at room temperature (about 23 to 25 degrees centigrade) for a period of four hours. Th'ereu'pon one milliliter of ethyl alcohol was added and the mixture diluted with fifty milliliters of water and extracted with three fifteen-milliliter portions of methylene chloride. The methylene chloride extracts were dried over anhydrous sodium sulfate, evaporated and the thus-obtained residue repeatedly recrystallized from methanol "to give 14- methylcortisone acetate 14a-me'thyl-l7a,21-dihydroxy-4- pregnene-3,11,'20-trione Zl-acetate) In the same manner, oxidizing other l te-methylhydrocortisone 21-acy1ate such as the 21-propi6nate, butyrate, valerate, hexanoate, heptanoate, octanoate, benzoate, phenylacetate, or the like with chromic anhydride, sodium or potassium dichromate in solutionjusually in acetic acid produces the corresponding 1'4amethylcorti'son'e 2l-acylate such as the 14a-methyl-17a,2l-dihydroxy-4-pregfiene- 3,11,20-trione 2l-propionate, trimethylacetate, butyrate, isobutyrate, valerate, hexanoate, heptanoate, octanoate, benzoate, phenylacetate, phenylpropionate, toluate, and the like.

Example 15.-14a-methylc0rtis0ne (14a-methyl-17a,21- dihydroxy-4-pregnene-3J1,20-tri0ne) A solution was prepared containing 0.1 gram of 14amethyl-17,21-dihydroxy-4-pregnene-3,l1,20-trione 2lacetate in ten milliliters of methanol. Through this solution was passed a stream of nitrogen for a period of ten minutes to purge the solution of oxygen from the air. Thereupon a similarly treated solution of 0.5 gram of potassium hydroxide in ten milliliters of methanol and one milliliter of water purged of air by passage of oxygenfree nitrogen was added to the first solution and the mixture allowed to stand at room temperature (about 25 degrees centigrade) for a period of three hours. The reaction mixture was thereupon poured into 100 milliliters of water, neutralized with dilute acetic acid and extracted with three 25-milliliter portions of methylene chloride. The combined methylene chloride extracts were dried over anhydrous sodium sulfate, evaporated and the thusobtained residue recrystallized three times from acetone Skellysolve B hexane to give 14a-methyl-17a,2l-dihydroxy-4-pregnene-3,11,20-trione l4a-methylcortisone) In the same manner other 2l-esters of 14a-methylcortisone can be hydrolyzed with a base to give the free diol, 14a-methyl-17a,2l-dihydroxy-4-pregnene-3,l 1,20-trione.

Exampe 16.14a-methylc0rtisone propionate (1 4a-methyl-1 70:,21 -dihydr0xy-4-pregnene-3,11,20-tri0ne 21 -pr0- pionate) A solution of 100 milligrams of 14a-methyl17a,21-dihydroxy-4-pregnene-3,11,20-trione in two milliliters of pyridine and two milliliters of propionic anhydride was allowed to stand for a period of eighteen hours overnight 1 1 at room temperature, (about 25 degrees centigrade). The mixture was thereupon poured into 75 milliliters of water, the precipitate collected on filter paper and recrystallized from methanol to give l4a-methylcortisone 21-propionate (l4a-methyl-17a,2l-dihydroxy-4-pregnene-3,11,20 trione 2l-propionate) Example 1 7 14a-methylcortis0ne l4ot-methylcortisone isovalerate,

(e) hexanoyl chloride yielded l4a-methylcortisone hexanoa-te, t a

(f) heptanoyl bromide yielded heptanoate, i

(g) octanoyl chloride yielded l4a-methylcortisone oc- 14a-methylcortisone I tanoate,

(h) benzoyl chloride yielded l4a-methylcortisone benzoate,

(i) phenylacetyl chloride yielded 14a-methylcortisone phenylacetate,

(i) phenylpropionyl chloride yielded 14a-methylcortisone phenylpropionate,

(k) 2-furoyl chloride yielded 14a-methylcortisone (2- furoate),

(l) nicotinyl chloride yielded 14a-methylcortisone nicotinate,

(m) toluenesulfonyl chloride yielded 14u-methy1cortisone toluenesulfonate,

(n) trimethylacetyl chloride-yielded l4u-methylcorti sone trimethylacetate,

lla-methylcortisone (o) dineopentylacetyl chloride yielded 14a-methylcortisone dineopentylacetate, and

(p) tertiarybutylacetyl chloride yielded 14u-methylcortisone tertiarybutyl acetate.

In the same manner as shown in Example 17, using anhydrides or acid halides of other organic acids to esterify l4a-methylcortisone, produces such esters as the 21- isobutyrate, cinnamate, acid tartrate, acid succinate, acid maleate, fl-cyclopentylpropionate, benzenesulfonate, anisate, para-chlorobenzenesulfonate, 3,5-dinitrobenzenesulfonate, fluoroacetate, chloroacetate, bromoacetate, i0do acetate, and the like.

It is to be understood that this invention is not to be limited to the exact details of operation or exact compounds shown and described as obvious modifications and equivalents will be apparent to one skilled in the art and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A steroid compound selected from the group consisting of l4a-methyl-17u,2l-dihydroxy-4-pregnene-3,l1,20- trione, 14a-methyl-l7a,2l-dihydroxy-4-pregnene-3,l1,20- trione 21-acylate, l4a-methyl-l1fi,l7u,21-trihydroxy-4- pregnene-3,20-dione and 14e-methyl-11fi,17a,2l-trihydroxy-4-pregnene-3,20-dione 21-acy1ate, wherein the acyl radical is of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

2. 14a-methyl-17a,2l-dihydroxy-4-pregnene 3,11,20- trione.

3. 14e-methyl-17a,21-dihydroxy-4-pregnene 3,11,20- trione 2l-aeetate.

4. 14a-methyl-11B,17a,21-trihydroxy-4-pregnene 3,20- dione.

5. 14a-methyl-1113,17u,2l-trihydroxy-4-pregnene 3,20- dione 21-acetate.

6. 14e-methy1-1113,17a,2l-trihydroxy-4-pregnene 3,20- dione 2l benzoate.

No references cited. 

1. A STEROID COMPOUND SELECTED FROM THE GROUP CONSISTING OF 14A-METHYL-17A,21-DIHYDROXY-4-PREGNENE-3,11,20TRIONE, 14A-METHYL-17A,21-DIHYDROXY-4-PREGNENE-3,11,20TRIONE 21-ACYLATE, 14A-METHYL-11B,17A,21-TRIHYDROXY-4PREGNENE-3,20-DIONE AND 14A-METHYL-11B,17A,21-TRIHYDROXY-4-PREGNENE-3,20-DIONE 21-ACYLATE, WHEREIN THE ACYL RADICAL IS OF A HYDROCARBON CARBOXYLIC ACID CONTAINING FROM ONE TO TWELVE CARBON ATOMS, INCLUSIVE. 